Muscle 3243A→G mutation load and capacity of the mitochondrial energy‐generating system

Janssen, A.J.M.; Schuelke, Markus; Smeitink, Jan A.M.; Trijbels, Frans J.M.; Sengers, R. C. A.; Lucke, Barbara; Wintjes, Liesbeth T.; Morava, Éva; Engelen, B.G.M. van; Smits, B.W.; Hol, F.A.; Siers, Marloes H.; Laak, Henk ter; Knaap, Marjo S. van der; Spronsen, Francjan J. van; Rodenburg, Richard J.; Heuvel, Lambert P. van den

doi:10.1002/ana.21328

Cited by 25 publications

(15 citation statements)

References 48 publications

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“…The sensitivity of the assays used to determine this capacity, such as pyruvate oxidation, is much higher than that of the standard enzyme activity measurements. 22 However, the mechanism underlying the (near) normal enzyme activities in muscle is currently unclear. Adaptive processes (eg, compensatory changes in the levels of other translation factors), which can differ quantitatively and qualitatively between tissues and patients, are likely involved.…”

Section: Discussionmentioning

confidence: 99%

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

et al. 2010

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The mitochondrial translation system is responsible for the synthesis of 13 proteins required for oxidative phosphorylation (OXPHOS), the major energy-generating process of our cells. Mitochondrial translation is controlled by various nuclear encoded proteins. In 27 patients with combined OXPHOS deficiencies, in whom complex II (the only complex that is entirely encoded by the nuclear DNA) showed normal activities, and mutations in the mitochondrial genome as well as polymerase gamma were excluded, we screened all mitochondrial translation factors for mutations. Here, we report a mutation in mitochondrial elongation factor G1 (GFM1) in a patient affected by severe, rapidly progressive mitochondrial encephalopathy. This mutation is predicted to result in an Arg250Trp substitution in subdomain G' of the elongation factor G1 protein and is presumed to hamper ribosome-dependent GTP hydrolysis. Strikingly, the decrease in enzyme activities of complex I, III and IV detected in patient fibroblasts was not found in muscle tissue. The OXPHOS system defects and the impairment in mitochondrial translation in fibroblasts were rescued by overexpressing wild-type GFM1, establishing the GFM1 defect as the cause of the fatal mitochondrial disease. Furthermore, this study evinces the importance of a thorough diagnostic biochemical analysis of both muscle tissue and fibroblasts in patients suspected to suffer from a mitochondrial disorder, as enzyme deficiencies can be selectively expressed.

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Section: Discussionmentioning

confidence: 99%

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

et al. 2010

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“…Three patients (1-MM, 2-MM, and 3-MM) had heteroplasmic mitochondrial DNA mutations in which the mutation was in high abundance (Ͼ90%) in skeletal muscle and resulted in deficiency of respiratory chain complexes containing mitochondrially encoded subunits affected by the mutation. In patient 1-MM with a 3243AϾG mutation, enzymatic deficiency was most pronounced in complex I (27). In patient 2-MM with a cytochrome b mutation, the enzymatic block exclusively affected complex III (52).…”

Section: Subjectsmentioning

confidence: 94%

Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms

Heinicke

Taivassalo

Wyrick

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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-Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low V O2peak (28 Ϯ 9% of predicted) and exaggerated systemic O 2 delivery relative to O2 utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high V E/V O2peak, (MM ϭ 104 Ϯ 18; C ϭ 42 Ϯ 8, P Յ 0.001), and V E/V CO2peak, (MM ϭ 54 Ϯ 9; C ϭ 34 Ϯ 7, P Յ 0.01); a steeper slope of increase in ⌬V E/⌬V CO2 (MM ϭ 50.0 Ϯ 6.9; C ϭ 32.2 Ϯ 6.6, P Յ 0.01); and elevated peak respiratory exchange ratio (RER), (MM ϭ 1.95 Ϯ 0.31, C ϭ 1.25 Ϯ 0.03, P Յ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower Pa CO 2 and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated V E/V O2, V E/V CO2, and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.hyperventilation; lactic acidosis; metaboreflex; exercise; oxidative phosphorylation EXERTIONAL DYSPNEA WAS FIRST described as a symptom that limited exercise in mitochondrial myopathy (MM) in patients with a familial disorder studied by Linderholm and coworkers in the 1960s (36, 38), a disease now recognized to be attributable to a mutation in the iron-sulfur cluster scaffold (ISCU) gene (40, 42) and associated with deficiency of multiple iron-sulfur proteins, including succinate dehydrogenase and aconitase (20,21). Exertional dyspnea has since been described as a dominant feature of exercise intolerance in other mitochondrial myopathies that severely restrict muscle oxidative phosphorylation (3a, 22). Moreover, mitochondrial disease has been suggested to be an underrecognized cause of unexplained exertional dyspnea (16,25), although, these reports lacked genetic confirmation and, in most cases, did not include biochemical assessment to indicate the presence and severity of the putative mitochondrial defect (16). To better define the physiological manifestations of exertional dyspnea in mitochondrial myopathy, we have evalu...

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“…The complete theory of this method is available in Janssen et al [28]. Here we show, for the first time, measurements of MEGS in spermatozoa, slightly modifying and combining the methods frequently used in skeletal muscle and fibroblasts [28,35,36]. The MEGS capacity was measured in spermatozoal homogenates, unlike the postnuclear fraction routinely used in skeletal muscle tissue analyses.…”

Section: Resultsmentioning

confidence: 96%

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

Křížová

Stufkova²,

Rodinová³

et al. 2017

Neurodegener Dis

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Background: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. Objective: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin. Methods: Semen samples from 12 TgHD and wild-type animals, aged 12-65 months, were obtained repeatedly during the study. Respiration was measured by polarography, MM was assessed by the detection of oxidation of radiolabeled substrates (mitochondrial energy-generating system; MEGS), and the content of the oxidative phosphorylation system subunits was detected by Western blot. Three possibly interfering factors were statistically analyzed: the effect of HD, generation and aging. Results: We found 5 MM parameters which were significantly diminished in TgHD spermatozoa and propose 3 specific MEGS incubations and complex I-dependent respiration as potential biomarkers of HD in TgHD spermatozoa. Conclusions: Our results suggest a link between the gain of toxic function of mutated huntingtin in TgHD spermatozoa and the observed MM and/or glycolytic impairment. We determined 4 biomarkers useful for HD phenotyping and experimental therapy monitoring studies in TgHD minipigs.

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Muscle 3243A→G mutation load and capacity of the mitochondrial energy‐generating system

Cited by 25 publications

References 48 publications

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

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